This proposal will continue the development and optimization of an innovative potential clinical treatment for asthma. Although there are a multitude of different possible triggers of an acute asthmatic attack, one defining feature of all such attacks is excessive contraction of the smooth muscle in the airway wall. Despite this common end point, most of the clinical asthma research and therapies in recent years have focused on understanding the immunologic factors that often lead to asthmatic attacks. Relatively little new research has focused directly on directly trying to limit this excessive smooth muscle contraction during an asthmatic attack. To this end, existing work supported by the current grant has already demonstrated the ability of this exciting new innovative method of treating the airway smooth muscle to permanently limit the ability of airway smooth muscle to shorten. This competitive renewal describes new objectives involving the optimization of the device that is used to deliver the RF energy to the smooth muscle, a procedure that is termed bronchial thermoplasty. It also involves new modeling and experimental work employing state of the art quantitative imaging to assess the effectiveness of these treatments in vivo. The project involves a close working partnership between the physiologic laboratories and expertise at the Johns Hopkins University and Asthmatx, Inc., the company that provides the mechanical and bioengineering skills involved in product development. The overall hypothesis governing this proposal is that, the treatment of airway smooth muscle with this innovative system will reduce asthma severity caused by smooth muscle contraction, regardless of the initiating stimulus for contraction. This approach has recently been validated in pilot study in 16 asthmatic subjects. In this proposal, three Specific Aims will be directed toward addressing this hypothesis. The first aim will use mathematical modeling to ascertain how the radiofrequency (RF) treatment energy spreads in radial and axial directions along the airway tree. The second aim will use the knowledge gained from this modeling to test new devices to deliver RF energy to the airway smooth muscle. The third aim will determine the impact of clinically relevant physiologic changes on treatment effectiveness. The studies proposed in this BRP will thus allow optimization of a device that has the potential to effectively cure all forms of human asthma regardless of the etiology.